The present invention relates to the field of pharmacological compositions and methods of utilizing such compositions in order to improve the flow of both naturally occurring fluids and pharmacologic agents through the mammalian eustachian tube.
Otitis media is a pathological condition common to mammalian species and most common to children. During episodes of otitis media, fluid accumulates in the middle ear or, as it is also known, the tympanic cavity.
Acute otitis media is a condition in which fluid accumulation in the middle ear is accompanied by signs or symptoms of ear infection (including both viral and bacterial etiologies). Such pathology may exhibit a bulging eardrum accompanied by pain or, in some instances, perforation of the tympanic membrane. Such perforations may also be accompanied by drainage of purulent material. In contrast, otitis media with effusion is typified by fluid accumulation within the tympanic cavity without signs of infection.
Both acute otitis media and otitis media with effusion may cause substantial pain as pressure increases, positively or negatively, within the confines of the tympanic chamber. Antibiotics, steroids, and antibiotics in combination with steroids have been utilized to treat otitis media. Antihistamine/decongestants have also been utilized in the treatment of otitis media with effusion.
The anatomical features of the middle ear define what can be described as a sealed chamber. On its lateral border, the middle ear is effectively isolated from the external auditory meatus (in the absence of a punctured ear drum), by the tympanic membrane. Medially, the middle ear is effectively sealed from the inner ear by a bony wall. The posterior wall of the tympanic cavity communicates with a large, but effectively sealed mastoid antrum. Only the anterior wall of the middle ear contains a passageway for effective communication outside of the tympanic cavity. There, a natural pathway provided by the auditory or, as it is also known, the eustachian tube, provides communication with the nasopharynx.
As stated above, during episodes of acute otitis media, the painful increased middle ear pressure may naturally resolve through a resultant perforation of, and drainage through, the tympanic membrane. However, the increased fluid pressure associated with otitis media with effusion does not resolve via this mechanism. In fact, for those patients suffering otitis media for prolonged periods of time, and especially for those evidencing significant associated hearing loss, myringotomy with the placement of a tympanostomy tube may be indicated as a means of equalizing middle ear pressure and in order to restore normal hearing. Recently, laser surgery has also been utilized to provide an aperture through the tympanic membrane through which the fluid trapped within the middle ear may drain. Besides the perforations of the eardrum provided by infection (acute otitis media), myringotomy and laser surgery, the eustachian tube, a natural middle ear drainage path described above, is provided by mammalian anatomy. Unfortunately, during episodes of otitis media with effusion (OME), a time when the natural pathway and pressure relief functions of the eustachian tube would be most useful, the increase pressure required to open the lumen (as described in more detail above and below), effectively eliminates this means of relieving middle ear pressurization. Reduced patency of the eustachian tube is believed to be one of the primary causes of OME in pediatric patients. In fact, it is known that OME elevates eustachian tube opening pressure independent of other pathological conditions effecting this conduit. The term xe2x80x9copening pressurexe2x80x9d as it is utilized throughout this disclosure and within the claims, refers to the pressure, typically measured in millimeters of mercury, necessary to cause the lumen of the auditory tube to open and provide a patent pathway between the nasopharynx and tympanic cavity.
Treatment of otitis media by means of administration of anti-inflammatory agents, antibiotics, decongestants and/or anti-histamines, or combinations thereof, is limited in effectiveness as, in the absence of perforation, there is presently no method for direct application of such drugs directly to target tissues of the eustachian tube and/or middle ear. Systemic applications of drugs via parenteral or oral routes, while eventually reaching the eustachian tube and middle ear, may have adverse systemic effects and, more importantly, are not especially effective at delivering a concentrated dose of the applicable drugs where they are truly needed, directly to the target tissues. Simply put, the sealed chamber anatomy of the middle ear has, up until the present time, constituted a barrier to direct drug application.
Although the central lumen of the eustachian tube does provide a pathway to the tympanic cavity, it is, as described below, ordinarily closed and resistant to fluid passage due to its inherent anatomical configuration. During episodes of otitis media, the relatively high surface tensions present at the air/liquid interface located upon the epithelial lining of the tube lumen further increase the opening pressure required to open this channel. Although direct application of therapeutically active agents, effective in the treatment of otitis media, to the lumen of the eustachian tube, and via the lumen to the middle ear, would be highly advantageous in treating otitis media, no method or composition has yet been disclosed capable of overcoming the surface tension within the tube lumen so as to facilitate opening of the tube and transport of such drugs throughout the lumen and on to the tissues of the middle ear. What is needed is a composition and method of applying same, especially formulated and adapted to decrease the surface tension of the auditory tube so as to decrease the opening pressure thereof, thereby providing a patent conduit for therapeutic agents, effective in the treatment of otitis media, to travel through said tube to effectively treat said condition.
Pathological conditions can arise from, and can cause changes in surface tension values of air/liquid interfaces in other organs of mammalian anatomy. The naturally occurring xe2x80x9csurfactant systemxe2x80x9d secreted upon the epithelial lining of the lung which is deficient in cases of R.D.S. is known to be comprised of a complex mixture of lipids, proteins and carbohydrates (as described in a recent review: Surfactants and the Lining of the Lung, The John Hopkinds University Press, Baltimore, 1988). The prime function of the surfactant system is to stabilize the alveoli and associated small airways against collapse by decreasing the surface tension at the air/liquid interface. It is now believed that the action of the phospholipid component of the surfactant system is the principal source of the powerful surface tension reduction effect of the naturally occurring surfactant system of the lung. More specifically, it is known that the fully saturated diacylphospholipids, principally, dipalmitoyl phosphatidylcholine (DPPC) provide liquid balance and anti-collapse properties to the lung""s epithelial lining. In addition to DPPC, spreading agents, also found within the naturally occurring surfactant system, assist DPPC in rapidly forming a uniform spread film on the air/liquid surfaces of the lung. Such spreading agents include cholesteryl esters such as, for example, cholesteryl palmitate (CP); phospholipids such as, for example, diacylophosphatidylglycerols (PG), diacylphosphatidylethanolamines (PE), diacylphosphatidylserines (PS), diacylphosphatidylinositols (PI), sphingomelin (Sph) and Cardiolipin (Card); and virtually and other phospholipid, and of the lysophospholipids; or any of the plasmalogens, dialklylphospholipids, phosphonolipids, carbohydrates and proteins, such as, for example, albumin, pulmonary surfactant proteins A, B, C and D. The naturally occurring surfactant system is further described in U.S. Pat. No. 5,306,483.
DPPC has been administered to infants with respiratory distress syndrome as a therapeutic measure. For this purpose, DPPC has been administered by means of an aqueous aerosol generator (utilized with an incubator in which the infant resided during treatment). Endotracheal administration has also been utilized. DPPC therapy has been typified as utilizing natural surfactants (harvested from porcine or bovine lungs), or artificial, commercially synthesized compounds.
It has also heretofore been disclosed to utilize therapeutic agents, in combination with surfactant/spreading agents to effectively administer drug therapy uniformly throughout the epithelial lining of the lung. U.S. Pat. No. 5,306,483 (the xe2x80x9c""483 patentxe2x80x9d) discloses a process to prepare lipid crystalline figures in fluorocarbon propellants for the delivery of therapeutically active substances which form amorphous fluids on delivery at the air/liquid interface of the lung and which can be utilized as an effective drug delivery system. More specifically, said patent discloses a process comprising (a) preparing a mixture of one or more lipids of the group of phospholipids known as phosphatidylcholines and one or more spreading agents, in powder form and a therapeutically active substance and one or more fluorocarbon propellants, said lipids, spreading agents and therapeutically active substances being insoluble in the propellants; and (b) evaporating the propellants from the mixture. The ""483 patent teaches the combination of dipalmitoyl phosphatidylcholine (DPPC) or any of the other fully saturated Acyl chain phospholipids, 80.0 to 99.5% by weight, and other spreading agents, for example, phospholipids such as, but not limited to PG, PE, PS, PI, lysophospholipids, plasmalogens, dialkylphospholipids, diether phosphonolipids, Cardiolipin, sphingomyelin, 0.5 to 20.0% weight, neutral lipids like cholesteryl esters such as, but no limited to, cholesteryl palmitate, cholesteryl oleate, cholesteryl stearate or mixtures thereof, 0.5 to 10% by weight, carbohydrates, such as, but not limited to, glucose, fructose, galactose, pneumogalactan, dextrose (or mixtures thereof), 0.5 to 10% by weight, and proteins such as, but not limited to albumin, pulmonary surfactant specific proteins A, B, C, and D 0.5 to 10% by weight, compounds in lipid-crystalline structures in fluorocarbon (both chloro- and hydrofluorocarbon) propellants in which therapeutically active agents, drugs and other materials can be carried into the lungs after release from and through metered dose nebulizer. The spreading agents referred to in the ""483 patent are compounds such as the above-described phospholipids, lysophospholipids, plasmalogens, dialklyphospholipids, phosphonolipids, carbohydrates and proteins. The function of the spreading agent is to assist DPPC, or other phospholipids such as, for example, DPPG, in rapidly adsorbing and forming a spread film upon the air/liquid surfaces of the lungs. In addition, the ""483 patent also discloses a process for preparing such lipid crystalline figures in fluorocarbon propellants without a therapeutically active substance for use as a tear (as for the eye).
Although the ""483 patent does disclose a process for preparing a drug delivery system especially adapted for uniformly applying a therapeutic agent to the epithelial lining of the lung, heretofore, no method or composition has been disclosed in the past that is particularly adapted, configured and formulated for the delivery of therapeutic agents to target tissues of the eustachian tube, or, via the eustachian tube, the middle ear.
Otitis media can, due to fluid accumulation, cause significant pressure, both positive and negative, in the afore-mentioned confines of the middle ear. Pressure differentials between the middle ear and the surrounding atmosphere, whether due to the addition of such fluids, or due to the relative decrease or increases of ambient atmospheric pressure, can cause great pain and discomfort. Such pressure conditions subject the tympanic membrane, and the associated pain receptors, to bulging and stretching. In addition, the accumulation of fluids, and the resulting static tension applied to the tympanic membrane, can greatly reduce hearing.
As mentioned above, the eustachian tube is specifically adapted to provide communication between the middle ear (a sealed chamber), and ambient atmospheric pressure, by providing a pathway between the tympanic cavity and the nasopharynx. Thus the auditory tube serves as a pressure equalization means for the middle ear. However, in order to provide this equalization function, and, at the same time, allow proper middle ear sound conduction, the eustachian tube, and the pathway it provides between the middle ear and the nasopharynx, are ordinarily closed. The lumen of the tube, as discussed below, is ordinarily open only during the act of swallowing and other movements that cause contraction of the attached musculature.
In humans, the eustachian tube is, on the average, 3.5 cm in length. The posterior one third of the tube is comprised of a bony wall with the anterior two thirds of the tubular structure being cartilaginous in composition. The auditory tube provides, by means of a central lumen, a fluid passage way between the nasopharynx and middle ear. However, the somewhat flattened medial and lateral walls of the tube are ordinarily in direct contact occluding and effectively limiting passage of liquids and gasses therethrough and allowing optimal sound conduction function of the middle ear which requires a sealed chamber. During swallowing, the tensor veli palatini muscle, which inserts into the lateral surface of the cartilaginous portion of the tube, contracts and pulls the wall of the tube laterally opening the central lumen thereby providing the communicating pathway needed for fluid flow between the middle ear and the nasopharynx. The action of the muscle upon the tube is needed to overcome the surface tension attracting the flattened medial and lateral walls of the central lumen together as well as the elastic recoil of the tube cartilage which also tends to close the lumen. The surface tension is due to the sero-mucous secretions found on the epithelial lining of the lumen.
In normal physiologic function, the sero-mucous secretions of the auditory tube, and the relatively low surface tensions they produce at the lateral and medial walls of the lumen, do not interfere with the normal opening and related pressure equalization functions of the auditory tube. However, middle ear, tube and upper respiratory infections and/or inflammatory conditions, such as allergies, can greatly effect the nature and increase the amount of the secretions found upon the lumen surface. Generally, such pathologic conditions greatly increase the surface tension of the lumen walls by increasing the relative amount of mucoid secretions, effectively interfering with, or completely preventing the opening of the tube. In addition, the tissues of the eustachian tube may become inflamed and engorged with fluids and cause further increases in opening pressures.
The above-described alterations in the nature and amount of secretions as well as inflammation of tube tissues are common during episodes of otitis media. Therefore, at a time when eustachian tube drainage of the middle ear would be highly desirable, this normally effective physiologic means of eliminating painful pressure often associated with such pathology is either hindered or completely eliminated. The common cold, flu, hay fever and other allergies can also result in eustachian tube failure for the same reason. However, inflammatory changes in tube tissues and lumen secretions are not the exclusive cause of such auditory tube failures.
Rapid changes in ambient pressure may also inhibit or completely prevent normal equalization functions of the auditory tube. If ambient pressure changes too quickly, the pressure gradient between the atmosphere and tympanic cavity may be too great to allow lumen opening. For example, the pressure within the tympanic cavity of a diver who, for example, ascends from a relatively deep dive without effectively and continuously equilibrating his or her middle ear through action of the eustachian tube (by swallowing, wiggling the jaw or utilizing other means to contract the attached musculature) can experience terrific pain know as a xe2x80x9csqueezexe2x80x9d which may be very difficult to overcome. Such situations are more likely in such instances when, for example, a diver engages in such activity, wisely or unwisely, while he is or she is suffering from an allergy or cold (for the above-described reasons). By rising in depth without frequent and effective eustachian tube function, the relatively low ambient pressure surrounding the diver effectively seals off the eustachian tubes communication with the relatively highly pressurized middle ear. A diver, under such circumstances, may simply descend back a few feet to a depth where the pressure gradient is non-existent or minimal, and thereby lower the opening pressure of the auditory tube allowing it to open and equalize the tympanic cavity. However, a passenger on a plane is in no position to change altitudes to obtain a xe2x80x9csecond chancexe2x80x9d to equilibrate. If such a passenger is unable to frequently and effectively equilibrate the middle ear during altitude changes due to, for example, increased secretions within the tube resulting from a cold, he or she is forced to bear significant pain.
Although, as described below, surfactant compositions, both natural and artificial, have been heretofore known, formulated and utilized to decrease surface tension within the lung, no such compositions, processes or methods for administering said compositions, have been heretofore suggested, taught or disclosed in regards to decreasing the surface tension within the lumen of the eustachian tube. Likewise, no method has heretofore been known which provides an effective decrease in opening resistance of the eustachian tube while simultaneously providing the delivery of therapeutically active agents, effective in the treatment of otitis media directly to the epithelial lining of the eustachian tube and middle ear.
Now, in accordance with the present invention, a method of increasing and enhancing mammalian eustachian tube lumen patency and pressure equalization performance is disclosed.
In a first preferred embodiment of the present invention, a mixture of one or more lipids and one or more spreading agents selected from the group consisting of sterols, lipids, fatty acids, cholesteryl esters, phospholipids, carbohydrates, and proteins, all in powder form, and one or more propellants is prepared. The propellant is selected to be one in which the one or more lipids and one or more spreading agents are not soluble so as to enable, in part, the formation of the below-described lipid crystals. Propellants such as, for example, fluorocarbon propellants may be advantageously selected. The lipids and the spreading agents are likewise advantageously selected to be insoluble in the propellants.
The lipid surfactants utilized in practicing the method of the present invention are selected to be present in an amount sufficient to effectively reduce the surface tension of the liquid/air interface of the epithelial surface to which they are applied, while the spreading agents are present in an amount sufficient to effectively distribute the lipids upon said surface. The term, xe2x80x9ceffectively reduce surface tensionxe2x80x9d as utilized throughout this application and in the claims, refers to that weight percentage range of lipid which, when present in said mixture of lipid crystals, provides a clinically significant decrease in eustachian tube opening pressure so as to allow increased pressure equalization function. The term, xe2x80x9ceffectively distribute the lipids upon said surfacexe2x80x9d refers to that weight percentage range of spreading agent that is required in order to provide adequate spreading and distribution of the lipids so as to form an amorphous spread film upon the epithelial lined surfaces of the lumen so that the lipid surfactant effects sufficient lumenal surface area enabling the afore-mentioned reduction in opening pressure.
It has been found that the above-described clinically significant decrease in eustachian tube opening pressure and effective distribution of lipids can be effected by a mixture comprised of from about 99.99 to about 30 weight percent lipid surfactant and from about 70 to about 0.01 spreading agent. Increased effectiveness is provided by a preferred mixture comprised of from about 99.99 to about 50 weight percent lipid surfactant and from about 50 to about 0.01 weight percent spreading agent, both based on total weight of the mixture. However, it is still further preferred that the lipid surfactants utilized in practicing the method of the present invention are present in an amount of about 80 to 99.5 percent by weight and the spreading agents are present in an amount of about 0.5 to about 20 percent by weight, both based upon the total weight of the mixture. Combination of the one or more lipids, one or more spreading agents and one or more propellants results in the formation of lipid crystals described in more detail, below. A metered dose of the mixture of lipid crystals is then administered, via inhalation through an external airway, into a mammal upon which the present method is practiced. It is preferred that the mixture be administered via a nasal orifice. However, it is also contemplated that the mixture of lipid crystals may also be administered via oral inhalation.
Upon administration, the propellant(s) are evaporated from the mixture and the lipid crystals are deposited at a nasopharyngeal, or as it may also be described, an anterior terminus, of a subject mammalian eustachian tube whereupon said lipid crystals come into contact with lumen surfaces of the tube. Upon contact with the air/liquid interfaces of the eustachian tube lumen, the mixture of lipid crystals forms an amorphous spread film upon said air/liquid interface effectively decreasing the opening pressure thereof.
The lipid crystals deposited upon the lumen surfaces and air/liquid interface thereupon is comprised of one or more lipids which are advantageously selected to demonstrate powerful surfactant activity. In addition, the spreading agent combined therewith provides substantially complete distribution of the surfactant over and upon the air/liquid interface resident upon the epithelial lining thereby resulting in a substantial decrease in lumen opening pressure. In turn, the decrease in lumen opening pressure results in greater patency of the eustachian tube and provides a resultant increase in fluid conduction/equalizing function of this anatomical structure.
In a second preferred embodiment of the present invention, a method of administering therapeutically active agents, effective in the treatment of otitis media, directly to mammalian eustachian tube and middle ear target tissues as well as a process for preparing a medicament for providing such treatment is disclosed. In the second embodiment of the present invention, a mixture of one or more lipids, one or more spreading agents, one or more therapeutically active agent(s), effective in the treatment of otitis media, and one or more propellants is prepared. The one or more lipids and spreading agents are advantageously selected from the group consisting of lipids, fatty acids, cholesteryl esters, phospholipids, carbohydrates, and proteins, all being in powder form. The one or more lipid surfactant, spreading agents and therapeutically active agent(s), effective in the treatment of otitis media, and the propellants are selected so that the lipid surfactants and spreading agents are insoluble in the propellants. The lipids utilized in practicing the method of the second preferred embodiment of the present invention are selected to be present in an amount sufficient to effectively reduce the surface tension of the liquid/air interface of the epithelial lining to which they are applied, while the spreading agents are present in an amount sufficient to effectively distribute the lipids to form an amorphous spread film upon said surface, while not adversely increasing surface tension. Effective reduction of surface tension is evidenced, as discussed below, in increased eustachian tube patency.
It has been found that the above-described clinically significant decrease in eustachian tube opening pressure and effective distribution of lipids can be effected by a mixture comprised of from about 99.99 to about 30 weight percent lipid surfactant and from about 70 to about 0.01 spreading agent. However, it is preferred, and increased effectiveness is provided by a mixture comprised of from about 99.99 to about 50 weight percent lipid surfactant and from about 50 to about 0.01 weight percent spreading agent, both based on total weight of the mixture. However, it is still further preferred that in practicing the method of the second embodiment of the present invention, the lipid surfactants are present in an amount of about 80 to 99.5 percent by weight and the spreading agents are present in an amount of about 0.5 to about 20 percent by weight, both based upon the total weight of said mixture. The mixture resulting from the combination of lipid surfactant(s), spreading agent(s) and therapeutically active agent and propellant forms lipid crystals which act as carriers for said therapeutically active agent. A metered dose of the mixture of lipid crystals is then administered, preferably via an external nasal airway, into a mammal upon which the method is practiced. A suitable bottle equipped with a metered dose valve and nasal administration adaptor is advantageously utilized for this purpose. However, all embodiments of the present invention also contemplate administration via oral inhalation of said mixture.
Upon administration of the lipid crystal mixture, the propellants, carry the lipid crystals in combination with therapeutically active agent(s) effective in the treatment of otitis media to the nasopharyngeal terminus of the eustachian tube whereupon the propellant(s) evaporate. The lipid crystals and therapeutically active agent is then deposited upon the tissues of the eustachian tube, including the epithelial lined lumen, whereupon the mixture forms an amorphous spread film effectively carrying said therapeutically active agent effective in the treatment of otitis media to the epithelial lining of the eustachian tube lumen and target tissues of the eustachian tube and middle ear. As stated in further detail below, the therapeutically active agent is advantageously selected to be effective in the treatment of otitis media. Therefore, the second preferred method of the present invention provides a method of administering therapeutically active agents directly to lumen surfaces of mammalian eustachian tubes, and also, by means of said eustachian tube lumen, to middle ear target tissues wherein said therapeutically active agents provide effective treatment for otitis media while, in addition, providing the same increased eustachian tube patency and performance as the first embodiment.
The lipid crystals deposited upon the lumen surfaces and air/liquid interface thereof are comprised of one or more lipids which are advantageously selected to demonstrate powerful surfactant activity and to serve as a carrier for selected therapeutic agent(s). In addition, the spreading agent deposited therewith provides effective distribution of the surfactant and therapeutic agent(s) throughout the lumen air/liquid surface to form an amorphous spread film thereupon resulting in substantial decreases in lumen opening pressure. In turn, the decrease in lumen opening pressure provides greater patency of the eustachian tube. Thus a resultant increase in fluid conduction/equalizing function of this anatomical structure is provided while simultaneously providing direct application of therapeutically active agent to target tissues of the auditory tube and middle ear.
The lipids utilized in practicing the method and process of the present invention may be advantageously selected to be phospholipids, neutral lipids or mixtures thereof. The phospholipids utilized may be further advantageously selected to be any phospholipid of the class known as phosphatidlycholine including any fully saturated diacyl phosphatidlycholine including 1,2 dipalmitoyl phosphatidylcholine (DPPC); a diacylphosphatidylglycerol; a diacylphosphatidylethanolamine; a diacylphosphatidylserine; a diacylphosphatidylinositol; sphingomyelin, Cardiolipin, lysophospholipid; a plasmalogen; a diether phosphonolipid; or a dialklyphospholipid.
The lipids utilized in practicing the method and process of the present invention may also be advantageously selected to be either plant or animal sterols. For example, cholesterol, cholecalciferol and ergosterol may be selected. In addition fatty acids, such as, for example, palmitic acid and oleic acid may also be selected.
The cholesteryl esters utilized in practicing the method of the present invention may be advantageously selected to be, for example, cholesteryl palmitate, cholesteryl oleate, cholesteryl stearate or mixtures thereof. Carbohydrates utilized in the present invention may be advantageously selected to be, for example, glucose, fructose, galactose, pneumogalactan, dextrose or mixtures thereof. Proteins especially suited and advantageously selected for use in the present invention include albumin, pulmonary surfactant specific proteins A or B or C or D, their synthetic analogs, and mixtures thereof.
As stated in further detail below, the therapeutically active agent is advantageously selected to be effective in the treatment of otitis media as well as agents effective in the treatment of the underlying causes thereof provoking said immune responses leading to the above-described inflammatory responses. For example, such agents may be selected to be effective in the treatment of mycotic, viral or bacterial infections, (as well as combinations thereof) underlying and causative of said inflammatory reactions. Therefore, the second preferred method of the present invention provides a method of administering therapeutically active agents directly to the epithelial lining of the eustachian tube wherein said therapeutically active agents provide effective treatment for the subject inflammatory condition such as, for example edemaxe2x80x94as well as the underlying causes thereofxe2x80x94while, simultaneously, the mixture of lipid crystals act to directly and effectively decrease the surface tension of the lumen.
In a first alternate embodiment of the present invention, a compound, process and method is disclosed providing administration of therapeutically active agents, effective in the treatment of otitis media, directly to mammalian eustachian tube and middle ear target tissues as well as a process for preparing a medicament for providing such treatment. In practicing the method and process of the first alternate embodiment of the present invention, a mixture of one or more lipid surfactants, one or more therapeutically active agent(s), effective in the treatment of otitis media, and/or the underlying cause thereof, and one or more propellantsxe2x80x94in which said lipid surfactant and therapeutically active agents are not solublexe2x80x94is prepared. The lipid surfactant is selected from the group consisting of sterols, lipids, fatty acids, cholesteryl esters, phospholipids, carbohydrates and proteins. The therapeutic agent may be selected from any of the afore or below-mentioned therapeutically active agents so as to provide desired therapeutic effects (regarding treatment of inflammatory conditions and the causative agents thereof). In such embodiments the mixture of lipids is comprised of a lipid surfactant and a therapeutic agent and the lipid surfactant and therapeutic agent are advantageously selected to be present in the same weight ratios as those described above and below in regards to those embodiments incorporating surfactant/spreading agent componentsxe2x80x94the therapeutic agent being present in the same respective weight percentage range as the spreading agent in such embodiments. For example, an effective result may be provided by a mixture comprised of from about 99.99 to about 30 weight percent lipid surfactant and from about 70 to about 0.01 therapeutic agent. Increased effectiveness is provided by a preferred mixture comprised of from about 99.99 to about 50 weight percent lipid surfactant and from about 50 to about 0.01 weight percent therapeutically active, both based on total weight of the mixture. However, it is still further preferred said mixture may be comprised of from about 80 to about 99.5 weight percent lipid surfactant and from about 20 to about 0.5 weight percent therapeutically active agent, based upon total weight of said mixture.
In practicing the first alternative embodiment, the therapeutically active agent may be selected as a pharmacologic agent which, in addition, is also selected from the group consisting of sterols, lipids, fatty acids, cholesteryl esters, phospholipids, carbohydrates and proteins. In such embodiments, the therapeutically active agent acts in accordance with its own pharmacologic function, as well as providing spreading agent function.
As described above, the therapeutic agent is selected to be present within the above-described weight ranges and in an amount sufficient to treat the afore-mentioned otitis media inflammatory condition and/or causative agents. The remainder of the mixture is comprised of one or more of the above-described lipid surfactants which act to reduce the surface tension of the liquid/air interface of the epithelial lining of the eustachian tube, while the therapeutically active agent provides treatment of the inflammatory condition effecting the eustachian tube, and/or the causative agents thereof. Upon evaporation of the propellant, an aerosolized mixture of lipid crystals is formed.
Upon administration of the mixture of lipid crystals and therapeutic agent to the eustachian tube via, for example, a metered dose bottle, the lipid crystal come into contact, and form an amorphous spread film upon the air/liquid interface resident upon the epithelial lining thereof. The surfactant spread film reduces the surface tension of the lumen while simultaneously delivering the therapeutic active agents to the afore-mentioned target tissues. The propellants may be advantageously selected to be fluorocarbon propellants such as, for example, chlorofluorocarbon propellants, hydrofluorocarbons or mixtures thereof. The present invention contemplates the use of carbon dioxide as a propellant as a suitable propellant. It is also contemplated that the present invention may incorporate and select any pharmaceutical grade, hypo-allergenic propellant in which the other components of the mixture are not solublexe2x80x94the propellant, lipids, spreading agents and therapeutically active agents must be selected so none of the afore-mentioned surfactants, spreading agents or therapeutically active agents are soluble, and thus dissolved, within the propellant. The propellant is thus selected in order to enable the formation of the aerosolized mixture of lipid crystals, discussed below.
Throughout this specification and claims, the phrase xe2x80x9ctherapeutically active agentxe2x80x9d includes any substance which is capable of altering a biologic, physiologic and/or immunologic function, in nature or degree and includes those substances generally referred to pharmacologic agents, drugs and gene therapy agents; the term xe2x80x9cfluorocarbonsxe2x80x9d includes the class of both chlorofluorocarbons and hydrofluorocarbons; the term lipids includes the class of phospholipids including, but not limited to PC, PG, PE, PI and Cardiolipin; and the phrase xe2x80x9cspreading agent(s)xe2x80x9d refer to and includes PG, PE, PS, PI, Sph., Card., lysophospholipids, plasmalogens, dialkylphospholipids, and all others in the class phospholipid as well as cholesteryl esters (like CP), proteins and carbohydrates.
Throughout this specification and claims, the phrase xe2x80x9cspreading agent(s)xe2x80x9d refers to compounds, as listed above, which assist the one or more lipid surfactants such as, for example, DPPC, in rapidly adsorbing and forming an amorphous spread film on air/liquid interfaces such as that found upon the epithelial lined lumen of the auditory tube. In addition, the compounds referred to as xe2x80x9cspreading agent(s)xe2x80x9d, together with the one or more lipids, are responsible for achieving and maintaining biophysical properties including, but not limited to, reduction of intermolecular attractive forces, surface tension, and the resultant attractive forces generated thereby, that tend to cause opposed surfaces, such as the lateral and medial epithelial lined lumen walls of the auditory tube, to adhere to each other. As discussed below, in certain preferred embodiments of the present invention, the therapeutically active agent(s) is advantageously selected from the group consisting of sterols, lipids, fatty acids, cholesteryl esters, phospholipids, carbohydrates, and proteins, all in powder form. In such embodiments, the therapeutic agent(s) provides, in addition to the above-described pharmacologic effects, the functions of the spreading agent (without need for a separate spreading agent.)
The major lipid component utilized in practicing a preferred embodiment of the present invention is advantageously selected to be phospholipid 1,2 dipalmitoyl, phosphatidlycholine (DPPC). DPPC is the most surface active of the phospholipids or any of the subclass of fully saturated acyl chain phospholipids. That is to say that DPPC, in combination with any spreading agent(s) disclosed herein, has a maximum effect in reducing surface tension at an air/liquid interface.
Another, minor lipid component that also acts as a spreading agent for the major component is advantageously selected to be diacylphosphatidylglycerol (PG). The number of carbon atoms in the acyl chains R and Rxe2x80x2, (see PG formula below) can vary between 8 and 22 and may or may not be fully saturated. DPPC and PG can be synthesized. However, since DPPC and PG are the main phospholipid constituents of cells, they are also readily extractable from such cells by non-polar solvents, i.e., chloroform, ether, acetone. DPPC""s structural formula is: 
and PG""s structural formula is: 
Phospholipids such as DPPC and CP may be obtained commercially, in a highly purified form from Fluka Chemical Co. of Ronkonkoma, N.Y.; Sigma Chemical CO. of St. Louis Mo.; and Avanti Polar Lipids of Birmingham, Ala. and Primedica of Cambridge, Mass.
DPPC and PG are preferred component(s) advantageously utilized in the present inventions methods for administering therapeutically active agents to the middle ear and auditory tube. In addition, these lipids increase the pressure equalizing performance of the auditory tube by direct result of their surfactant qualities. DPPC may be selected to be present in the composition over a fairly wide range. It is preferred that weight percentages of from about 80% to about 99.5% DPPC by is selected. However, the DPPC component may be selected to be present in an amount of from about 99.99% to about 50% by weight without undue interference in desired properties needed for drug delivery and surfactant activity.
Throughout this specification and in the claims, the phrase xe2x80x9cincreasing pressure equalization performance of the auditory tubexe2x80x9d and xe2x80x9cincreasing the pressure equalization performance of the eustachian tubexe2x80x9d both refer to the increased ease and ability of a mammal upon which the present method is practiced, to utilize the pathway provided by the lumen of the eustachian tube to equalize the pressure of the middle ear with ambient pressure surrounding the mammal. The increased ease and ability is the result of the decrease in opening pressure of the lumen of the mammalian eustachian tube provided by the present invention.
Another lipid that can be utilized in practicing the methods of the present invention is cholesteryl palmitate (CP), which also serves as a spreading agent. This cholesteryl ester is a neutral lipid which belongs to a class of organic compounds that are also cell constituents and are extractable by non-polar solvents such as chloroform, methanol, ether, etc. The structural formula of CP is: 
CP may be obtained commercially in a highly purified form from Fluka Chemical Co. and Sigma Chemical Co. The CP component constitutes a minor portion of the composition. It is selected to be present in a weight percentage sufficient so as to enable effective spread and distribution of the lipid upon the mucosal surfaces. It is preferred that the CP component be selected to be present in an amount ranging from about 0.5% to 20% by weight. Also, the preferred ratio of DPPC to CP is from about 99.5 DPPC to 0.5 CP by weight. However, the CP component may be selected to be present in an amount of from about 50 to about 0.01% by weight and the DPPC component may be selected to be percent in an amount of from about 99.99% to about 0.50 weight % without undue interference in desired properties needed for drug delivery and surfactant activity.
The term xe2x80x9ctherapeutically active agentxe2x80x9d and xe2x80x9ctherapeutically active agent effective in the treatment of otitis media,xe2x80x9d as utilized in and throughout this specification and claims, refers to those drugs effective in treatment of otitis media including, but not limited to anti-inflammatory agents including, for example, betamethasone, including, for example, betamethasone dipropionate and betamethasone valerate as well as all other effective formulations; de-congestive agents such as phenylephrine, including, for example, phenylephrine HCL and phenylephrine bitartrate and all other effective formulations thereof; antibiotics including, for example erythromycin, amoxicillin, zythromax, and augmentin (amoxicillin and clavuliic acid) in all of their effective formulations and gene therapy agents. Such gene therapy agents, as the term is used herein, refers to a biochemical substancexe2x80x94as well as vectors thereofxe2x80x94selected from the group including, but not limited to, proteins, peptides or amino acids; nucleic acids such as DNA, including full length genes or fragments thereof derived from genomic, cDNA, or artificial coding sequences, gene regulatory elements, RNA including mRNA, tRNA, ribosomal RNA, ribozymes and anitsense RNA, oligonucleotides, oligoribonucleotides, deoxyribonucleotides and ribonucleotides as such agents may exist as isolated and purified compounds or in unpurified mixtures, such as tissue, cell or cell lysate. In addition, such agents may be naturally occurring, synthetic, or a mixture thereof. The term xe2x80x9call of their effective formulationsxe2x80x9d as used throughout this specification and in the claims refers to those specific species of a particular therapeutic agent effective in the treatment of otitis media.
The combination of lipid component(s) and spreading agent component(s) disclosed herein, may be referred to, collectively, as the xe2x80x9ccarrierxe2x80x9d when said combination is mixed with a therapeutically active agent so as to act as a carrier therefore. When practicing the method of the present invention wherein therapeutically active agents are administered directly to mammalian eustachian tube and middle ear tissues, it is preferred that carrier, the mixture of one or more lipids and one or more spreading agents, be comprised of a mixture of DPPC and CP in a 200:1 ratio (by weight). However, it has been found that a ratio range of from 5:1 to 300:1 (DPPC/CP) will also produce an effective carrier for this embodiment. If, for example, the therapeutic agent is selected to be betamethasone, the weight ratio of betamethasone to carrier (DPPC/CP) is advantageously selected to be 1 microgram betamethasone to 5 milligrams carrier. However, it has been found that a weight ratio range of 0.5 to 1000 micrograms betamethasone/5 milligrams carrier yields an effective and functional mixture.
In certain embodiments of the present invention, the therapeutically active agent is advantageously selected from the group consisting of sterols, lipids, fatty acids, cholesteryl esters, phospholipids, carbohydrates, and proteins, all in powder form. In such embodiments, in addition to acting as pharmacologic agents, drugs or a gene therapy modality, the therapeutically active agent also serves as a spreading agent. In such instances, any of the afore-mentioned surfactants of the present invention may be combined with a therapeutic agents selected from the above-identified group at the same weight ratio ranges selected for spreading agent/surfactant mixtures. Upon administration (and evaporation of propellant) a mixture of lipid crystals is formed that acts to decrease opening pressure of the eustachian tube while simultaneously carrying the therapeutically active agent to target tissues of the eustachian tube and middle ear.
When practicing the method of the present invention wherein the therapeutically active agent is selected to be phenylephrine it is preferred to select the weight ratio of phenylephrine to carrier to be 160 micrograms/995 milligrams. However, it has also been found that a weight ratio range of from 50 to 5000 micrograms (phenylephrine): 995 to 900 milligrams carrier, respectively, forms an effective mixture and functional mixture. The term xe2x80x9ceffective and functional mixturexe2x80x9d as utilized throughout this application and in the claims refers to the effectiveness of the mixture of lipid crystals in combination with said therapeutically active agent resulting from the combinations disclosed herein in: (a) reaching the target tissue of the eustachian tube and middle ear; (b) reducing the surface tension thereupon; and (c) delivering a uniform dose of therapeutic agent directly to and effectively spreading upon said tissues so as to effectively bring symptomatic relief and/or resolution of the afore-mentioned pathological conditions including otitis media.
When practicing the method of the present invention wherein the therapeutically active agent is selected to be the antibiotic erythromycin, the ratio of erythromycin to carrier is advantageously selected to be 200 mg antibiotic to 800 mg carrier (DPPC/CP) by weight. However, a weight range of from 50 to 200 mg erythromycin: from 950 to 800 mg carrier, respectively, has been found to be fully effective in practicing the present method.
The fluorocarbon propellants utilized in practicing certain preferred embodiments of the method of the present invention, namely: trichlorodifluoromethane, dichlorodifluoromethane, and tetrafluoromethane or mixtures thereof, which are commercially available from Union Carbide Corp., Danbury, Conn. and Armstrong Laboratories, West Roxbury Mass. are advantageously selected for formation of the lipid crystalline figures of the present invention. The fluorocarbon propellants are present over a range of 2 to 30 times the amount, by weight, of lipid, but components of lipid and fluorocarbon propellants both are needed in order to obtain the required lipid crystalline figures.
In practicing the methods of the present invention wherein therapeutically effective agents are administered directly to the middle ear for the treatment of otitis media, DPPC is advantageously selected as the major lipid component since the amphoteric nature of this phospholipid allows the molecule to act as a carrier for any drug or therapeutic agent. However, the presence of a charge on other lipid components (a negative charge on PG, for example) would alter and further improve the carrying capacity of the lipid crystals for a particular therapeutic agent.
In addition to erythromycin and amoxicillin, the method of the present invention also contemplates selecting zythromax and Augmentin (amoxicillin+clavulinic acid) as antibiotic therapeutic agents. However, because of the highly amphoteric nature of the carrier utilized herein, the use of any presently known and available, as well as antibiotic developed in the future capable of providing effective treatment of infections of the middle ear and eustachian tube are contemplated and fully functional with the methods and compositions herein.